Antibacterial therapeutic composition containing thiamphenicol derivative

ABSTRACT

A NEW THIAMPHENICOL DERIVATIVE HAS BEEN PREPARED, HAVING THE FORMULA:   H3C-SO2-1,4-PHENYLENE-CH(-OH)-CH(-NH-CO-CHCL2)-CH2-OOC-   -CH2-H3N(+).(-)OOC-CH(-CH2-SH)(-NH-CO-CH3)   WHICH IS WATER-SOLUBLE, TASTELESS, ODORLESS AND EXERCISES A STRONG MUCOLYTIC ACTION AS WELL AS AN ANTIBACTERIC ACTION HIGHER THAN THAT OF THE THIAMPHENICOL, WITH RESPECT TO MANY MICROORGANISMS WHICH ARE RESPONSIBLE FOR RESPIRATORY DISEASES.

r* 3,651,235 Patented Mar. 21, 1972 United States Patent a mucolytic agent and with a chemotherapeutic agent 3,651,235 having wide range of action. But heretofore such a treat- ANTIBACTERIAL THERAPEUTIC COMPOSITION ment could not be realized with acetylcysteine for the CONTANNG THIAMPHENICOL DERIVATIVE following reasons. Pencillin and b acitracin are inactivated Uberto M. Teotino Milan Italy assignor to Whitefin V Holding 1 Lugano,switzefland 5 by the acetylcysteine and vlce versa (The Journal of No Drawing Original application Mar. 9 1966 Ser. Pediatrics 62, 35, 1963), streptomycin cannot be used as 532 383 Patent 3,542 854 hated 24, an aerosol spray because it lnvolves the danger of local 197i). Divided and this application Man 1 1970 reactions and sensitizations (new England J. Med. 237,

N 24,333 683-692, 1947; I.A.'M.A. 138, 640-41, 1948); chloro- Int. Cl. A611: 27/00 10 amphenicol cannot be used since it is water-insoluble US. Cl. 424-311 2 C almS (Merck Index, 7th ed. p. 234), whilst its soluble derivatives, such as the sodium salts of its monosuccinic ester, have an unbearablybitter taste; the tetracyclines, for ABSTRACT OF THE DISCLOSURE their part, cannot be used because of their irritating action A new thiamphenicol derivative has been prepared, having the formula:

OH d-threo N HCOCH;

which is water-soluble, tasteless, odorless and exercises a strong mucolytic action as well as an antibacteric action higher than that of the thiamphenicol, with respect to many microorganisms which are responsible for respiratory diseases.

on the mucous membranes and on the tissues they contact.

Therefore, the only solution possible for carrying out at the same time a treatment with acetylcysteine and a chemotherapeutic agent was to associate it with chemotherapeutic products with limited spectrum. This application is a division of application Ser. No. We have now found the compound having the formula:

532,883, filed Mar. 9, 1966, now Pat. 3,542,854 issued which is water-soluble, tasteless, odorless, and exercises Nov.24, 1970. 5 a strong mucolytic action and an antibacteric action The present invention relates to a new compound, higher than that of the thiamphenicol with respect to particularly useful in the therapeutic field for all the many germs which are responsible for respiratory disclinical forms characterized by the presence of thick and eases, without, however, exhibiting any of the abovemenviscous secretions, where infective processes are in course tioned inconveniences. Furthermore, the compound of or it is wanted to prevent their appearance. the present invention does no more exhibit the unpleas- It is known that acetylcysteine is a therapeutic agent ant sulphurous odor characteristic of acetylcysteine. This endowed with marked mucolytic power (US. Pat. No. compound, therefore, possesses all the therapeutic and 3,091,569) which can be favorably used for topical treatorganoleptic requisites required for the topical treatment, ment of respiratory diseases showing the presence of in particular as an aerosol spray, of all those respiratory viscous secretions, although its use is in part prejudiced diseases which are characterized by the contemporaneous owing to its unpleasant odor. However, there are frepresence of infective centers and viscous secretions. quent cases in which the presence of viscous secretions is The new therapeutic product of the present invention concomitant with an infective process. In such cases the can be prepared according to the following procedure: topical treatment with an antibacteric agent is hindered 6.4 g. of d-threo 1-(p-methylsulfonylphenyl)-2-diby the mucous barrier, while, on the other hand, the chloro-acetamido-3-amino-acetoxy-1-propanol and 2.5 g. treatment with a mucolytic agent does not resolve the of N-acetyl-l-cysteine are dissolved in 350 ml. of anhyinfective process. Therefore it would be desirable to carry drous methyl alcohol. The solution thus obtained is deout the topical treatment contemporaneously both with colored with carbon and filtered- The filtrate is concen- 3 trated in vacuo, up to dryness. The residue is taken up with 25 ml. of anhydrous methyl alcohol and 150 ml. of anhydrous ethyl ether, and then filtered. The residue is washed again with a small amount of ether, and dried in vacuo. 7.20 g. of product are thus obtained.

Analysis.Calculated (percent): N, 7.29; Cl, 12.3; S, 11.12. Found (percent): N, 7.35; Cl, 12.3; S, 11.03.

The compound thus obtained is a white microcrystalline powder, which is odorless and tasteless.

It contains 61.5% of thiamphenicol and 28.31% of acetylcysteine. Its molecular weight is 576.49, melting point=l58-160 C. (with decomposition) and it is strongly soluble in water even at room temperature; in ethyl alcohol it dissolves only at its boiling point. The 10% aqueous solution has a pH of 4.6.

PHARMACOLOGY Acute toxicity When injected in rats intraveneously at the rate of 120 mg./kg./min., the DL is 1547 mg./kg. The toxic symptoms are tremors, dispnea, convulsions.

Chronic toxicity The tests of chronic toxicity on adult rats were carried out by aerosol treatment with aqueous solutions for minutes every day for more than 4 weeks. The histologic study of the lungs, trachea, bronchia, larynx, liver, kidneys and blood of the animals thus treated, did not reveal any alteration.

Action on blood pressure, breathing and isolated heart The tests carried out on rabbits under anaesthesia showed, at the intravenous dose of 40 mg./kg., a slowing down of the respiratory movements and a slight reduction of the blood pressure; these efiects, however, disappeared rapidly.

Antibacterial activity in vitro Thiamphenicol glycinate and acetylcysteinate of thiamphenicol glycinate were tested parallely on various bacteria stocks generally belonging to kinds or types of the saprophytic and pathogenic flora of human respiratory ducts, such as kleibsielle, streptococcus, dyplococcus, and staphylococcus.

We have used the method of increasing a liquid medium solution. The tubes sown with the germs to be tested were placed, under anaerobic conditions, in an oven at 37 C. over 18 hours: after this time the bacteriostatic concentration was observed. The culture medium used was the Brain Heart Infusion to which was added defibrinized mutton blood in amount of 10 percent (for dyplococcus and streptococcus). The bacteriostatic concentrations of the two substances, expressed in micro g. per ml. of medium, proved with respect to the microbic species that the antibacteric activity of the acetylcysteinate of thiamphenicol glycinate was higher by 20 to 50% than the antibacteric activity of the thiamphenicol glycinate alone.

Taking into account that the N-acetylcysteinate has no antibacteric action and that the cysteinate of thiamphenicol glycinate has just the same activity of the thiamphenicol alone, the increased activity of the N- acetylcysteinate of thiamphenicol glycinate is quite surprising.

CLINICAL TESTS The compound of the present invention was administered by aerosol and by bronchial instillation in various acute and chronic diseases of the respiratory apparatus characterized by the presence of mucous and of mucopurulent secretions and by an infective component.

The fluidification of the secretions was rapid and sharp and was constantly accompanied by attenuation or by disappearance of the purulent component and of the phlogistic picture.

The amount of expectoration became more abundant 4 during the first days of the treatment and diminished by and by, and finally disappeared.

The fluidification of the bronchial secretion has always facilitated in a determinant way the opening up of the bronchia, either spontaneously or by bronchous inspiration, with considerable positive effects on the respiratory function and improvement or resolution of the local as well as general clinical picture.

MEDICINE AND PHTHISIOLOGY The treatment of patients affected by acute and subacute bronchitis, asthmatic bronchitis, bronchioectasy, lung abscesses, tuberculosis with superposed aspecific infections, etc., has produced a sharp diminution or disappearance of the dyspnea, cyanosis, cough and fever, with positive effects also on the general conditions.

The favorable clinical results were confirmed also by laboratory tests, radiographic examinations and by thoracic semiology.

SURGERY The compound of the present invention may prevent and heal complications of obstruent or infective character in the respiratory ducts (atelectasis, lung abscesses, bronchopneumonia, etc.) which often occur after thorax operations or operations in other places. The necessity of practising broncho-inspirations was markedly reduced and, if same were made necessary due to the presence of a severe organic illness, they were always facilitated.

Moreover, it must be pointed out that the treatment with the compound of the present invention has most probably avoided the tracheostomy in a patient affected by severe myastheny.

OTORHINOLARYNGOLOGY The compound has proved to be of extreme utility both as prophylactic and curative medicine for obstruent and infective complications of the respiratory apparatus which often appear in subjects bearing a cannula or suffering tracheal stomatitis.

TOLERANCE The clinical tests have confirmed the excellent tolerance of the compound, the appearance of collateral effects of irritative and bronchospastic type being practically absent.

Bronchoscopic tests carried out on patients before and after prolonged treatments did not demonstrate any modification of the respiratory mucous membrane.

INDICATIONS The compound of the present invention is useful for all clinical forms characterized by the presence of thick and viscous secretion where infective processes are in course or where it is wished to prevent the arising thereof, such as the following applications:

Medicine: Acute and chronic bronchitis, bronchopneumonia and pneumonia with slow evolution, lung abscess, emphysema, atelectasy.

Surgery: Prophylaxis and treatment of broncho-pneumonia complications due to surgical interventions (thoracic, abdominal operations, etc.); bronchopneumonia, atelectasy, lung abscess. Facilitation of bronchoinspiration handling during anaesthesia and post-operative course, and prophylaxis of infective complications.

Otorhinolaryngology: Catarrhal and purulent otitis, tubal infections, rhinopharyngitis, laryngotracheitis. Prophylaxis and treatment of obstruent and infective complications subsequent to tracheostomy, preparation for the bronchoscopy, bronchography, and broncho-inspiration.

Phthisiology: Aspecific infective forms with bronchial catarrh associated with pulmonary consumption. Retention of secretions with unsufiicient drainage of cavity lesions.

Podiatry: Bronchitis and bronchopneumonia with particular reference to those having slow evolution, bronchiolitis, whooping cough, mucoviscidosis. Some forms of asphyxia of new-born babies.

DIRECTIONS AND DOSES The compound of the present invention may be administered via aerosol, by endobronchial instillation, endoauricular or other cavities instillation or washings by means of pharmaceutical forms generally used for these kinds of administration.

By way of a non-limitative example we cite one of the processes by which a pharmaceutical form can be prepared which is suitable for the following purpose:

400 g. of the compound according to the present invention are dissolved in 4 litres of water; the solution thus obtained is filtered through a Seitz filter, and subdivided in 1000 flasks having ml. capacity.

The 1000 flasks are placed in a lyophilizer and on completion of the lyophilization they are closed with pierceable rubber stoppers, and sealed.

At the moment of use, 3 to 5 ml. of a physiological solution are introduced into the flask, which is then agitated. In this way a limped solution is obtained which must be used within 4 to 5 days.

For aerosol administration For an adult, one or two applications per day for 5 to days or more, depending on the evolution of the clinical form, of nebulized 3 to 5 ml. of physiological solution containing 400 mg. of the compound, are recommended. For children, the above dose is halved.

For endobronchial instillation According to the chosen administration method (permanent probes, or bronchoscope, etc.), 400 to 800 mg. of compound in 6 to 11 m1. of physiological solution each time, are administered once or twice per day, depending on requirement.

For instillations or endoauricular washing or washing of other cavities The average dosage is 200 mg. of compound in 1.5 to 2.5 ml. of physiological solution.

What is claimed is:

1. An antibacterial therapeutic composition containing, as the principal active ingredient, a compound of the formula:

in an aqueous vehicle at a concentration of 66-133 mg./ml.

2. An antibacterial therapeutic composition in unit dosage form containing 400 mg. of the compound in 4 ml. of the aqueous vehicle.

References Cited UNITED STATES PATENTS OTHER REFERENCES Chemical Week, Mar. 16, 1968, pp. 39-40.

JEROME D. GOLDBERG, Primary Examiner 

